Cerebellar volume and cerebellocerebral structural covariance in schizophrenia: a multisite mega-analysis of 983 patients and 1349 healthy controls.

Although cerebellar involvement across a wide range of cognitive and neuropsychiatric phenotypes is increasingly being recognized, previous large-scale studies in schizophrenia (SZ) have primarily focused on supratentorial structures. Hence, the across-sample reproducibility, regional distribution, associations with cerebrocortical morphology and effect sizes of cerebellar relative to cerebral morphological differences in SZ are unknown. We addressed these questions in 983 patients with SZ spectrum disorders and 1349 healthy controls (HCs) from 14 international samples, using state-of-the-art image analysis pipelines optimized for both the cerebellum and the cerebrum. Results showed that total cerebellar grey matter volume was robustly reduced in SZ relative to HCs (Cohens's d=-0.35), with the strongest effects in cerebellar regions showing functional connectivity with frontoparietal cortices (d=-0.40). Effect sizes for cerebellar volumes were similar to the most consistently reported cerebral structural changes in SZ (e.g., hippocampus volume and frontotemporal cortical thickness), and were highly consistent across samples. Within groups, we further observed positive correlations between cerebellar volume and cerebral cortical thickness in frontotemporal regions (i.e., overlapping with areas that also showed reductions in SZ). This cerebellocerebral structural covariance was strongest in SZ, suggesting common underlying disease processes jointly affecting the cerebellum and the cerebrum. Finally, cerebellar volume reduction in SZ was highly consistent across the included age span (16-66 years) and present already in the youngest patients, a finding that is more consistent with neurodevelopmental than neurodegenerative etiology. Taken together, these novel findings establish the cerebellum as a key node in the distributed brain networks underlying SZ.

Proprioception in motor learning: lessons from a deafferented subject.

Proprioceptive information arises from a variety of channels, including muscle, tendon, and skin afferents. It tells us where our static limbs are in space and how they are moving. It remains unclear however, how these proprioceptive modes contribute to motor learning. Here, we studied a subject (IW) who has lost large myelinated fibres below the neck and found that he was strongly impaired in sensing the static position of his upper limbs, when passively moved to an unseen location. When making reaching movements however, his ability to discriminate in which direction the trajectory had been diverted was unimpaired. This dissociation allowed us to test the involvement of static and dynamic proprioception in motor learning. We found that IW showed a preserved ability to adapt to force fields when visual feedback was present. He was even sensitive to the exact form of the force perturbation, responding appropriately to a velocity- or position-dependent force after a single perturbation. The ability to adapt to force fields was also preserved when visual feedback about the lateral perturbation of the hand was withdrawn. In this experiment, however, he did not exhibit a form of use-dependent learning, which was evident in the control participants as a drift of the intended direction of the reaching movement in the perturbed direction. This suggests that this form of learning may depend on static position sense at the end of the movement. Our results indicate that dynamic and static proprioception play dissociable roles in motor learning.

A 7T fMRI study of cerebellar activation in sequential finger movement tasks.

We investigated whether higher activation of the cerebellar cortex in unpredictable compared to predictable sequential finger movements reflects higher demands in motor response selection or also increases in demands on motor sequencing. Furthermore, we asked the question whether the cerebellar nuclei show a similar or reversed response profile as the cerebellar cortex. Ultra-high-field 7T functional magnetic resonance imaging was performed in nineteen right-handed, healthy young participants. Tasks involved finger tapping of a constant sequence, a random sequence, and with one finger at a time (no sequence). Conditions involved the same number of movements of fingers II-V. The three tasks were accompanied by the activation of the known hand areas within the cerebellar cortex and dentate nuclei. Activation of the cerebellar cortex and the dorsorostral dentate was significantly increased in the random-sequence condition compared to both the constant-sequence and the no-sequence conditions, with no significant difference between the constant-sequence and the no-sequence conditions. Error rate and movement frequency was not significantly different between conditions. Thus, differences between conditions cannot be explained by differences in motor execution. Because no difference was observed between the no-sequence and the constant-sequence conditions, increased cerebellar activation in the random-sequence condition likely reflects increased demands in motor response selection. Co-activation of cerebellar cortex and nuclei may be a consequence of excitatory afferent collaterals to the nuclei, "rebound-firing" of dentate neurons, and/or inhibitory synaptic input from Purkinje cells.

Grip force regulates hand impedance to optimize object stability in high impact loads.

Anticipatory grip force adjustments are a prime example of the predictive nature of motor control. An object held in precision grip is stabilized by fine adjustments of the grip force against changes in tangential load force arising from inertia during acceleration and deceleration. When an object is subject to sudden impact loads, prediction becomes critical as the time available for sensory feedback is very short. Here, we investigated the control of grip force when participants performed a targeted tapping task with a hand-held object. During the initial transport phase of the movement, load force varied smoothly with acceleration. In contrast, in the collision, load forces sharply increased to very large values. In the transport phase, grip force and load force were coupled in phase, as expected. However, in the collision, grip force did not parallel load force. Rather, it exhibited a stereotyped profile with maximum ∼65 ms after peak load at contact. By using catch trials and a virtual environment, we demonstrate that this peak of grip force is pre-programmed. This observation is validated across experimental manipulations involving different target stiffness and directions of movement. We suggest that the central nervous system optimizes stability in object manipulation-as in catching-by regulating mechanical parameters including stiffness and damping through grip force. This study provides novel insights about how the brain coordinates grip force in manipulation involving an object interacting with the environment.

Imaging the deep cerebellar nuclei: a probabilistic atlas and normalization procedure.

The deep cerebellar nuclei (DCN) are a key element of the cortico-cerebellar loop. Because of their small size and functional diversity, it is difficult to study them using magnetic resonance imaging (MRI). To overcome these difficulties, we present here three related methodological advances. First, we used susceptibility-weighted imaging (SWI) at a high-field strength (7T) to identify the dentate, globose, emboliform and fastigial nucleus in 23 human participants. Due to their high iron content, the DCN are visible as hypo-intensities. Secondly, we generated probabilistic maps of the deep cerebellar nuclei in MNI space using a number of common normalization techniques. These maps can serve as a guide to the average location of the DCN, and are integrated into an existing probabilistic atlas of the human cerebellum (Diedrichsen et al., 2009). The maps also quantify the variability of the anatomical location of the deep cerebellar nuclei after normalization. Our results indicate that existing normalization techniques do not provide satisfactory overlap to analyze the functional specialization within the DCN. We therefore thirdly propose a ROI-driven normalization technique that utilizes both information from a T1-weighted image and the hypo-intensity from a T2*-weighted or SWI image to ensure overlap of the nuclei. These techniques will promote the study of the functional specialization of subregions of the DCN using MRI.

Evidence for a motor and a non-motor domain in the human dentate nucleus--an fMRI study.

Dum and Strick (J. Neurophysiol. 2003; 89, 634-639) proposed a division of the cerebellar dentate nucleus into a "motor" and "non-motor" area based on anatomical data in the monkey. We asked the question whether motor and non-motor domains of the dentate can be found in humans using functional magnetic resonance imaging (fMRI). Therefore dentate activation was compared in motor and cognitive tasks. Young, healthy participants were tested in a 1.5 T MRI scanner. Data from 13 participants were included in the final analysis. A block design was used for the experimental conditions. Finger tapping of different complexities served as motor tasks, while cognitive testing included a verbal working memory and a visuospatial task. To further confirm motor-related dentate activation, a simple finger movement task was tested in a supplementary experiment using ultra-highfield (7 T) fMRI in 23 participants. For image processing, a recently developed region of interest (ROI) driven normalization method of the deep cerebellar nuclei was used. Dorso-rostral dentate nucleus activation was associated with motor function, whereas cognitive tasks led to prominent activation of the caudal nucleus. The visuospatial task evoked activity bilaterally in the caudal dentate nucleus, whereas verbal working memory led to activation predominantly in the right caudal dentate. These findings are consistent with Dum and Strick's anatomical findings in the monkey.

Evolution of the cerebellar cortex: the selective expansion of prefrontal-projecting cerebellar lobules.

It has been suggested that interconnected brain areas evolve in tandem because evolutionary pressures act on complete functional systems rather than on individual brain areas. The cerebellar cortex has reciprocal connections with both the prefrontal cortex and motor cortex, forming independent loops with each. Specifically, in capuchin monkeys cerebellar cortical lobules Crus I and Crus II connect with prefrontal cortex, whereas the primary motor cortex connects with cerebellar lobules V, VI, VIIb, and VIIIa. Comparisons of extant primate species suggest that the prefrontal cortex has expanded more than cortical motor areas in human evolution. Given the enlargement of the prefrontal cortex relative to motor cortex in humans, our hypothesis would predict corresponding volumetric increases in the parts of the cerebellum connected to the prefrontal cortex, relative to cerebellar lobules connected to the motor cortex. We tested the hypothesis by comparing the volumes of cerebellar lobules in structural MRI scans in capuchins, chimpanzees and humans. The fractions of cerebellar volume occupied by Crus I and Crus II were significantly larger in humans compared to chimpanzees and capuchins. Our results therefore support the hypothesis that in the cortico-cerebellar system, functionally related structures evolve in concert with each other. The evolutionary expansion of these prefrontal-projecting cerebellar territories might contribute to the evolution of the higher cognitive functions of humans.

Ipsilateral corticospinal projections do not predict congenital mirror movements: a case report.

Congenital mirror movements (CMMs) are involuntary, symmetric movements of one hand during the production of voluntary movements with the other. CMMs have been attributed to a range of physiological mechanisms, including excessive ipsilateral projections from each motor cortex to distal extremities. We examined this hypothesis with an individual showing pronounced CMMs. Mirror movements were characterized for a set of hand muscles during a simple contraction task. Transcranial magnetic stimulation (TMS) was then used to map the relative input to each muscle from both motor cortices. Contrary to our expectations, CMMs were most prominent for muscles with the strongest contralateral representation rather than in muscles that were activated by stimulation of either hemisphere. These findings support a bilateral control hypothesis whereby CMMs result from the recruitment of both motor cortices during intended unimanual movements. Consistent with this hypothesis, bilateral motor cortex activity was evident during intended unimanual movements in an fMRI study. To assess the level at which bilateral recruitment occurs, motor cortex excitability during imagined unimanual movements was assessed with TMS. Facilitory excitation was only observed in the contralateral motor cortex. Thus, the bilateral recruitment of the hemispheres for unilateral actions in individuals with CMMs appears to occur during movement execution rather than motor planning.

Illusory conjunctions are alive and well: a reply to Donk (1999).

When presented with a red T and a green O, observers occasionally make conjunction responses and indicate that they saw a green T. These errors have been interpreted as reflecting separable processing stages of feature detection and integration with the illusory conjunctions arising from a failure at the integration stage. Recently, M. Donk (1999) asserted that the phenomenon of illusory conjunctions is an artifact. Conjunction reports are actually the result of confusing a nontarget item (O in the example above) for a target item (the letter T) and (correctly) reporting the color associated with the (incorrectly) selected target. The authors demonstrate that although target-nontarget confusion errors are a potential source of conjunction reports, there is a plethora of findings that cannot be accounted for by this confusion model. A review of the literature indicates that in many studies, illusory conjunctions do result from a failure to properly integrate features.

Moving to directly cued locations abolishes spatial interference during bimanual actions.

Interference is frequently observed during bimanual movements if the two hands perform nonsymmetric actions. We examined the source of bimanual interference in two experiments in which we compared conditions involving symmetric movements with conditions in which the movements were of different amplitudes or different directions. The target movements were cued either symbolically by letters or directly by the onset of the target locations. With symbolic cues, reaction times were longer when the movements of the two hands were not symmetric. With direct cues, reaction times were the same for symmetric and nonsymmetric movements. These results indicate that directly cued actions can be programmed in parallel for the two hands. Our results challenge the hypothesis that the cost to initiate nonsymmetric movements is due to spatial intetference in a motor-programming stage. Rather the cost appears to be caused by stimulus identification, response-selection processes connected to the processing of symbolic cues, or both.

Asymmetries in a unilateral flanker task depend on the direction of the response: the role of attentional shift and perceptual grouping.

Four experiments were conducted using a flanker task with 1 distractor appearing either on the left or right side of a central target. Responses were made on a keyboard aligned parallel to the displays. A larger flanker effect was obtained when the distractor was on the same side as the response. Two factors account for this asymmetry. First, when the flanker and target are identical, the 2 form a group that is assigned a spatial tag, creating a form of the Simon effect on the basis of the compatibility between the response keys and the group. Second, preparation of a lateralized response appears to entail a shift of visual attention in the corresponding direction, thus enhancing processing of the flanker on the response side. Consistent with the 2nd hypothesis, participants were more likely to correctly recognize letters that were briefly presented at the distractor position on the same side as the response.